Chlorin derivatives or pharmaceutically acceptable salts thereof, preparation method and use thereof, and combination thereof with an ultrasonic medical system

Abstract

The present disclosure relates to a chlorin derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, an anti-tumor composition including the chlorin derivative or the pharmaceutically acceptable salt thereof, use of the chlorin derivative or the pharmaceutically acceptable salt thereof in the treatment of a tumor, and a combination of the chlorin derivative or the pharmaceutically acceptable salt thereof and an ultrasound medical system. The chlorin derivative or the pharmaceutically acceptable salt thereof has a structure represented by formula (I), and the ultrasonic medical system comprises a transducer ultrasonic bed and a contact agent. The chlorin derivative of the present disclosure can be used in photodynamic therapy and sonodynamic therapy, thereby effectively inhibiting and treating cancer.

What is claimed is: 
     
       1. A chlorin or a pharmaceutically acceptable salt thereof having a structure represented by following formula (I): 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is 
       
       
         
           
           
               
               
           
         
          wherein R 14  is —H, C 1 -C 6  alkoxy or C 1 -C 4  haloalkyl; or 
       
       
         
           
           
               
               
           
         
          wherein n is any integer from 2 to 7; 
         R 2  is 
       
       
         
           
           
               
               
           
         
          C 1 -C 6  alkoxy or —OH, wherein R 8  is any of the following groups: 
       
       
         
           
           
               
               
           
         
         wherein R 9 , R 10 , R 11 , R 12  and R 13  may be the same or different, and are each independently selected from C 1 -C 6  alkyl, and 
         when R 2  is 
       
       
         
           
           
               
               
           
         
          R 3  and R 4  are each independently selected from C 1 -C 6  alkoxy or —OH; 
         when R 2  is C 1 -C 6  alkoxy or —OH, one of R 3  and R 4  is any of the following groups: 
       
       
         
           
           
               
               
           
         
         wherein R 9 , R 10 , R 11 , R 12  and R 13  are defined as above, and 
         the other of R 3  and R 4  is C 1 -C 6  alkoxy or —OH; and 
         M is 2H or a metal ion. 
       
     
     
       2. The chlorin or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the chlorin or the pharmaceutically acceptable salt thereof is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein, 
         R 1  is 
       
       
         
           
           
               
               
           
         
          wherein n is any integer from 2-7; 
         R 3 , R 4 , and R 3  are any one of the following groups: 
       
       
         
           
           
               
               
           
         
         wherein R 9 , R 10 , R 11 , R 12  and R 13  are defined as in  claim 1 ; and 
         M is defined as in  claim 1 . 
       
     
     
       3. The chlorin or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the chlorin or the pharmaceutically acceptable salt thereof is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein M is defined as in  claim 1 . 
       
     
     
       4. A method for preparing the chlorin or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the method comprises the steps of:
 a 1 : subjecting compound 1 to esterification reaction with an alcohol to obtain compound 2: 
 
       
         
           
           
               
               
           
         
         b 1 : subjecting compound 2 to condensation reaction with β-alanine tert-butyl ester hydrochloride in the presence of a condensation agent to obtain compound 3: 
       
       
         
           
           
               
               
           
         
         c 1 : subjecting compound 3 to olefin metathesis reaction with a substituted α-olefin 
       
       
         
           
           
               
               
           
         
          in the presence of a catalyst to obtain compound 4: 
       
       
         
           
           
               
               
           
         
         wherein R 1  is 
       
       
         
           
           
               
               
           
         
          wherein n is any integer from 2 to 7; 
         d 1 : subjecting compound 4 to hydrolysis reaction to obtain compound 5: 
       
       
         
           
           
               
               
           
         
         e 1 : subjecting compound 5 to condensation reaction with an amino acid ester hydrochloride in the presence of a condensation agent to obtain a compound of formula II(a): 
       
       
         
           
           
               
               
           
         
         wherein M is 2H, or a metal ion-upon reaction with a metal chloride or acetate complex, and wherein R 8  is defined as in  claim 1 ; and 
         optionally subjecting the compound of formula II(a) to hydrolysis reaction under alkaline conditions to obtain a corresponding salt, that is, a compound of formula II(b); 
         or alternatively, 
         a 2 : subjecting compound 1 to reaction with an alkyl halide under alkaline conditions to obtain compound 10: 
       
       
         
           
           
               
               
           
         
         b 2 : subjecting compound 10 to olefin metathesis reaction with a substituted α-olefin 
       
       
         
           
           
               
               
           
         
          in the presence of a catalyst to obtain compound 11: 
       
       
         
           
           
               
               
           
         
         wherein R 1  is 
       
       
         
           
           
               
               
           
         
          wherein n is any integer from 2 to 7, 
         wherein M is 2H, or a metal ion upon reaction with a metal chloride or acetate complex; 
         c 2 : subjecting compound 11 to hydrolysis reaction under alkaline conditions to obtain compound 13: 
       
       
         
           
           
               
               
           
         
         d 2 : subjecting compound 13 to condensation reaction with an amino acid ester hydrochloride to obtain a compound of formula III(a): 
       
       
         
           
           
               
               
           
         
         wherein M is 2H, or a metal ion upon reaction with a metal chloride or acetate complex, 
         wherein R 3  is defined as in  claim 1 ; and 
         optionally subjecting the compound of formula III(a) to hydrolysis reaction under alkaline conditions to obtain a corresponding salt, a compound of formula III(b); 
         or alternatively, 
         a 3 : subjecting compound 19 to condensation reaction with an amino acid ester hydrochloride in the presence of a condensation agent to obtain compound 20: 
       
       
         
           
           
               
               
           
         
         b 3 : subjecting compound 20 to olefin metathesis reaction with a substituted α-olefin 
       
       
         
           
           
               
               
           
         
       
       in the presence of a catalyst to obtain a compound of formula IV(a): 
       
         
           
           
               
               
           
         
         wherein R 1  is 
       
       
         
           
           
               
               
           
         
          wherein n is any integer from 2 to 7, 
         wherein M is 2H, or a metal ion upon reaction with a metal chloride or acetate complex, and wherein R 4  is defined as in  claim 1 ; and 
         optionally subjecting the compound of formula IV(a) to hydrolysis reaction under alkaline conditions to obtain a corresponding salt, that is, a compound of formula IV(b). 
       
     
     
       5. A pharmaceutical comprising the chlorin or the pharmaceutically acceptable salt thereof according to  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
       6. A method of treating a tumor comprising administering the chlorin or the pharmaceutically acceptable salt thereof according to  claim 1  to a subject having tumor cells, wherein the treatment is performed by photodynamic therapy or sonodynamic therapy. 
     
     
       7. The method according to  claim 6 , wherein the tumor comprises benign tumor and malignant tumor. 
     
     
       8. The method according to  claim 7 , wherein the photodynamic therapy is performed with light waves at a wavelength of 600-800 nm and the sonodynamic therapy is performed with ultrasounds at an intensity of 1.88 W/cm 2 . 
     
     
       9. A combination of a chlorin or a pharmaceutically acceptable salt thereof and an ultrasonic medical system, wherein
 the chlorin or the pharmaceutically acceptable salt thereof is the chlorin or the pharmaceutically acceptable salt thereof according to  claim 1 ; and 
 the ultrasonic medical system comprises a transducer ultrasonic bed and a contact agent, wherein the transducer ultrasonic bed comprises a bottom and a wall extending upward from the bottom; the bottom is provided, at positions corresponding to head, torso, and limbs of a subject, respectively, with at least one ultrasonic transducer for transmitting ultrasonic waves to the subject thereon; the wall is provided, at positions corresponding to the head and limbs of the subject, respectively, with at least one ultrasonic transducer for transmitting ultrasonic waves to the subject; and the contact agent is used to transmit ultrasonic waves between the subject and the ultrasonic transducers. 
 
     
     
       10. The combination according to  claim 9 , wherein the ultrasonic medical system further comprises a transducer module assembly, wherein the transducer module assembly is installed above the transducer ultrasonic bed and comprises at least one ultrasonic transducer for transmitting ultrasonic waves to the subject therebelow; and the contact agent is also used to transmit ultrasonic waves between the subject and the at least one ultrasonic transducer. 
     
     
       11. The combination according to  claim 10 , wherein the transducer module assembly further comprises a numerically controlled motion device for controlling the movement of the transducer module assembly in a horizontal and/or vertical direction. 
     
     
       12. The combination according to  claim 9 , wherein the ultrasonic wave is a pulse wave or a continuous wave. 
     
     
       13. The combination according to  claim 9 , wherein the contact agent is at least one of water and vacuum degassed cold/hot water. 
     
     
       14. The combination according to  claim 9 , wherein the ultrasonic medical system further comprises an automatic control system with a programmable logic controller, and a contact agent supply system, wherein,
 the contact agent supply system is connected to the transducer ultrasonic bed, so as to supply the contact agent to the transducer ultrasonic bed; and 
 the automatic control system with a programmable logic controller is respectively connected to the transducer ultrasonic bed, the transducer module assembly and the contact agent supply system, so as to control the supply of the contact agent from the contact agent supply system to the transducer ultrasonic bed, and to control the operation of at least some of the ultrasonic transducers in the transducer ultrasonic bed and in the transducer module assembly. 
 
     
     
       15. The combination according to  claim 14 , wherein the automatic control system with a programmable logic controller further comprises a monitoring system for displaying at least one of the following:
 a. working parameters of at least some of the ultrasonic transducers in the transducer ultrasonic bed and the transducer module assembly; and 
 b. lesion information within the subject. 
 
     
     
       16. The chlorin or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the metal ion is a divalent metal ion or a tetravalent metal ion. 
     
     
       17. The chlorin or the pharmaceutically acceptable salt thereof according to  claim 16 , wherein the divalent metal ion is selected from Cu 2+ , Fe 2+ , Zn 2+ , Mg 2+ , Ni 2+ , Co 2+ , Pt 2+  or Pd 2+ . 
     
     
       18. The chlorin or the pharmaceutically acceptable salt thereof according to  claim 16 , wherein the tetravalent metal ion is Sn 4+  or Ti 4+ . 
     
     
       19. The method according to  claim 4 , wherein the metal ion is a divalent metal ion or a tetravalent metal ion. 
     
     
       20. The method according to  claim 19 , wherein the divalent metal ion is selected from Cu 2+ , Fe 2+ , Zn 2+ , Mg 2+ , Ni 2+ , Co 2+ , Pt 2+  or Pd 2+ . 
     
     
       21. The method according to  claim 19 , wherein the tetravalent metal ion is Sn 4+  or Ti 4+ . 
     
     
       22. The pharmaceutical composition according to  claim 5 , the pharmaceutical composition is an injection formulation. 
     
     
       23. The method according to  claim 6 , wherein the chlorin or the pharmaceutically acceptable salt thereof is in a form of an injection formulation. 
     
     
       24. The method according to  claim 6 , wherein the tumor is carcinoma in situ. 
     
     
       25. The method according to  claim 24 , wherein the carcinoma in situ is selected from breast cancer, liver cancer, lung cancer, and colorectal cancer. 
     
     
       26. The method according to  claim 6 , wherein the tumor is cancer metastasis. 
     
     
       27. The method according to  claim 26 , wherein the cancer metastasis is selected from breast cancer metastasis, liver cancer metastasis, lung cancer metastasis, and colorectal cancer metastasis. 
     
     
       28. The method according to  claim 8 , wherein the photodynamic therapy is performed with light waves at a wavelength of 660 nm. 
     
     
       29. The combination according to  claim 12 , wherein the ultrasonic wave has a frequency of 0.3-3 MHz. 
     
     
       30. The combination according to  claim 12 , wherein the ultrasonic wave has a ultrasound intensity of 0.1-3 W/cm 2 .